Anti-PCSK9 antibodies, formulations, dosing, and methods of use

US 9,266,961 B2
Filed: 06/14/2013
Issued: 02/23/2016
Est. Priority Date: 06/15/2012
Status: Expired due to Fees

First Claim

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1. An anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody comprising a heavy chain and light chain variable domain comprising six hypervariable region (HVR) sequences:

(i) HVR-H1 comprising GFTFX₁X₂X₃X₄IH (SEQ ID NO;

28), wherein X₁is S or T;

X₂is G, R or S;

X₃is H, T or Y;

X₄is A or T;

(ii) HVR-H2 comprising RISPANGNTNYADSVKG (SEQ ID NO;

4);

(iii) HVR-H3 comprising WIGSRELYIMDY (SEQ ID NO;

5);

(iv) HVR-L1 comprising RASQDVSX₁AVA (SEQ ID NO;

29), wherein X₁is S or T;

(v) HVR-L2 comprising SASX₁LYS (SEQ ID NO;

30), wherein X₁is F or S; and

(vi) HVR-L3 comprising QQAYX₁X₂X₃X₄T (SEQ ID NO;

37), wherein X₁is P, R or T;

X₂is A, I, S or T;

X₃is L, P or Q;

X₄is A, H, P or S.

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Abstract

The invention provides anti-PCSK9 antibodies, formulations, dosing regimens, and methods of using the same.

111 Citations

42 Claims

1. An anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody comprising a heavy chain and light chain variable domain comprising six hypervariable region (HVR) sequences:
- (i) HVR-H1 comprising GFTFX₁X₂X₃X₄IH (SEQ ID NO;
  
  28), wherein X₁is S or T;
  
  X₂is G, R or S;
  
  X₃is H, T or Y;
  
  X₄is A or T;
  
  (ii) HVR-H2 comprising RISPANGNTNYADSVKG (SEQ ID NO;
  
  4);
  
  (iii) HVR-H3 comprising WIGSRELYIMDY (SEQ ID NO;
  
  5);
  
  (iv) HVR-L1 comprising RASQDVSX₁AVA (SEQ ID NO;
  
  29), wherein X₁is S or T;
  
  (v) HVR-L2 comprising SASX₁LYS (SEQ ID NO;
  
  30), wherein X₁is F or S; and
  
  (vi) HVR-L3 comprising QQAYX₁X₂X₃X₄T (SEQ ID NO;
  
  37), wherein X₁is P, R or T;
  
  X₂is A, I, S or T;
  
  X₃is L, P or Q;
  
  X₄is A, H, P or S.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 18)
- - 2. The antibody of claim 1, wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:
    - 1, SEQ ID NO;
      
      2 or SEQ ID NO;
      
      3, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO;
      
      4, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO;
      
      5.
  - 3. The antibody of claim 2, further comprising (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:
    - 6 or SEQ ID NO;
      
      7;
      
      (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO;
      
      8 or SEQ ID NO;
      
      26; and
      
      (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO;
      
      33.
  - 4. The antibody of claim 1, comprising (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:
    - 6 or SEQ ID NO;
      
      7;
      
      (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO;
      
      8 or SEQ ID NO;
      
      26; and
      
      (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO;
      
      33.
  - 5. The antibody of claim 1, wherein the antibody comprises:
    - (1) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;
      
      3;
      
      (2) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;
      
      4;
      
      (3) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;
      
      5;
      
      (4) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;
      
      7;
      
      (5) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;
      
      8; and
      
      (6) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;
      
      33.
  - 6. The antibody of claim 1, comprising a VH sequence of SEQ ID NO:
    - 17.
  - 7. The antibody of claim 1, comprising a VL sequence of SEQ ID NO:
    - 34.
  - 8. The antibody of claim 1, comprising a VH sequence of SEQ ID NO:
    - 17 and a VL sequence of SEQ ID NO;
      
      34.
  - 9. The antibody of claim 1, wherein the antibody is a monoclonal antibody.
  - 10. The antibody of claim 1, wherein the antibody is humanized.
  - 11. The antibody of claim 1, wherein the antibody is a human antibody.
  - 12. The antibody of claim 1, wherein the antibody is an antibody fragment selected from a Fab, Fab′
    - -SH, Fv, scFv or (Fab′
      
      )₂fragment.
  - 13. The antibody of claim 1, wherein at least a portion of the framework sequence is a human consensus framework sequence.
  - 14. The antibody of claim 1, comprising (i) a heavy chain comprising the amino acid sequence of SEQ ID NO:
    - 35 and a light chain comprising the amino acid sequence of SEQ ID NO;
      
      36, (ii) a heavy chain comprising amino acids 1-450 of SEQ ID NO;
      
      35 and a light chain comprising the amino acid sequence of SEQ ID NO;
      
      36, (iii) a heavy chain comprising amino acids 1-449 of SEQ ID NO;
      
      35 and a light chain comprising the amino acid sequence of SEQ ID NO;
      
      36, or (iv) the heavy and light chain of any one of (i), (ii), or (iii) wherein the proline at amino acid position 449 of SEQ ID NO;
      
      35 is amidated.
  - 17. An anti-preprotein convertase kexin type 9 (PCSK9) antibody produced by a method comprising culturing a host cell comprising a nucleic acid encoding the anti-PCSK9 antibody of claim 1 under conditions suitable for expression of the nucleic acid encoding the anti-PCSK9 antibody, and recovering the anti-PCSK9 antibody produced by the host cell.
  - 18. A pharmaceutical composition comprising the anti-PCSK9 antibody of claim 1 and a pharmaceutically acceptable carrier.

15. An anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody comprising (a) HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 5, (b) HVR-L3 comprising the amino acid sequence of SEQ ID NO;
  
  33, and (c) HVR-H2 comprising the amino acid sequence of SEQ ID NO;
  
  4.

16. An anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody comprising a light chain variable domain comprising the amino acid sequence of SEQ ID NO:
- 34.

19. A pharmaceutical composition comprising an anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody at 150 to 225 mg/mL, histidine acetate at 10 to 30 mM, arginine acetate at 150 to 170 mM, polysorbate at 0.01% to 0.03%, and pH at 5.8 to 6.2.
- View Dependent Claims (20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42)
- - 20. The composition of claim 19, wherein the anti-PCSK9 antibody comprises a variable domain comprising one, two, three, four, five, or six hypervariable region (HVR) sequences selected from the group consisting of:
    - (i) HVR-H1 comprising GFTFX₁X₂X₃X₄IH (SEQ ID NO;
      
      28), wherein X₁is S or T;
      
      X₂is G, R or S;
      
      X₃is H, T or Y;
      
      X₄is A or T;
      
      (ii) HVR-H2 comprising RISPANGNTNYADSVKG (SEQ ID NO;
      
      4);
      
      (iii) HVR-H3 comprising WIGSRELYIMDY (SEQ ID NO;
      
      5);
      
      (iv) HVR-L1 comprising RASQDVSX₁AVA (SEQ ID NO;
      
      29), wherein X₁is S or T;
      
      (v) HVR-L2 comprising SASX₁LYS (SEQ ID NO;
      
      30), wherein X₁is F or S; and
      
      (vi) HVR-L3 comprising QQSYX₁X₂X₃X₄T (SEQ ID NO;
      
      31) or QQAYX₁X₂X₃X₄T (SEQ ID NO;
      
      37), wherein X₁is P, R or T;
      
      X₂is A, I, S or T;
      
      X₃is L, P or Q;
      
      X₄is A, H, P or S.
  - 21. The composition of claim 19, wherein the anti-PCSK9 antibody or antibody fragment in the composition is at 200 mg/mL, histidine acetate in the composition is at 20 mM, arginine acetate in the composition is at 160 mM, and polysorbate 20 in the composition is 0.02%, and pH at 6.0.
  - 22. The composition of claim 19, wherein the composition is suitable for subcutaneous administration.
  - 23. The composition of claim 19, wherein the viscosity of the composition is less than 10 cP at 25°
    - C.
  - 24. The composition of claim 19, wherein the anti-PCSK9 antibody comprises a heavy chain and light chain variable domain comprising the following six hypervariable region (HVR) sequences:
    - (i) HVR-H1 comprising GFTFX₁X₂X₃X₄IH (SEQ ID NO;
      
      28), wherein X₁is S or T;
      
      X₂is G, R or S;
      
      X₃is H, T or Y;
      
      X₄is A or T;
      
      (ii) HVR-H2 comprising RISPANGNTNYADSVKG (SEQ ID NO;
      
      4);
      
      (iii) HVR-H3 comprising WIGSRELYIMDY (SEQ ID NO;
      
      5);
      
      (iv) HVR-L1 comprising RASQDVSX₁AVA (SEQ ID NO;
      
      29), wherein X₁is S or T;
      
      (v) HVR-L2 comprising SASX₁LYS (SEQ ID NO;
      
      30), wherein X₁is F or S; and
      
      (vi) HVR-L3 comprising QQSYX₁X₂X₃X₄T (SEQ ID NO;
      
      31) or QQAYX1X2X3X4T (SEQ ID NO;
      
      37), wherein X₁is P, R or T;
      
      X₂is A, I, S or T;
      
      X₃is L, P or Q;
      
      X₄is A, H, P or S.
  - 25. The composition of claim 24, wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:
    - 1, SEQ ID NO;
      
      2 or SEQ ID NO;
      
      3, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO;
      
      4, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO;
      
      5.
  - 26. The composition of claim 25, wherein the antibody further comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:
    - 6 or SEQ ID NO;
      
      7;
      
      (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO;
      
      8 or SEQ ID NO;
      
      26; and
      
      (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO;
      
      9, SEQ ID NO;
      
      10, SEQ ID NO;
      
      11, SEQ ID NO;
      
      12, SEQ ID NO;
      
      13, SEQ ID NO;
      
      14, or SEQ ID NO;
      
      33.
  - 27. The composition of claim 24, wherein the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:
    - 6 or SEQ ID NO;
      
      7;
      
      (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO;
      
      8 or SEQ ID NO;
      
      26; and
      
      (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO;
      
      9, SEQ ID NO;
      
      10, SEQ ID NO;
      
      11, SEQ ID NO;
      
      12, SEQ ID NO;
      
      13, SEQ ID NO;
      
      14, or SEQ ID NO;
      
      33.
  - 28. The composition of claim 24, wherein the antibody comprises:
    - (1) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;
      
      1;
      
      (2) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;
      
      4;
      
      (3) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;
      
      5;
      
      (4) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;
      
      7;
      
      (5) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;
      
      8; and
      
      (6) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;
      
      10.
  - 29. The composition of claim 24, wherein the antibody comprises:
    - (1) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;
      
      1;
      
      (2) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;
      
      4;
      
      (3) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;
      
      5;
      
      (4) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;
      
      7;
      
      (5) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;
      
      8; and
      
      (6) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;
      
      11.
  - 30. The composition of claim 24, wherein the antibody comprises:
    - (1) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;
      
      2;
      
      (2) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;
      
      4;
      
      (3) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;
      
      5;
      
      (4) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;
      
      7;
      
      (5) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;
      
      8; and
      
      (6) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;
      
      12.
  - 31. The composition of claim 24, wherein the antibody comprises:
    - (1) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;
      
      3;
      
      (2) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;
      
      4;
      
      (3) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;
      
      5;
      
      (4) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;
      
      7;
      
      (5) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;
      
      8; and
      
      (6) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;
      
      13.
  - 32. The composition of claim 24, wherein the antibody comprises:
    - (1) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;
      
      1;
      
      (2) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;
      
      4;
      
      (3) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;
      
      5;
      
      (4) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;
      
      7;
      
      (5) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;
      
      8; and
      
      (6) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;
      
      14.
  - 33. The composition of claim 24, wherein the antibody comprises:
    - (1) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;
      
      3;
      
      (2) an HVR-H2 comprising the amino acid sequence of SEQ ID NO;
      
      4;
      
      (3) an HVR-H3 comprising the amino acid sequence of SEQ ID NO;
      
      5;
      
      (4) an HVR-L1 comprising the amino acid sequence of SEQ ID NO;
      
      7;
      
      (5) an HVR-L2 comprising the amino acid sequence of SEQ ID NO;
      
      8; and
      
      (6) an HVR-L3 comprising the amino acid sequence of SEQ ID NO;
      
      33.
  - 34. The composition of claim 24, wherein the antibody comprises a VH sequence of SEQ ID NO:
    - 15, SEQ ID NO;
      
      27, SEQ ID NO;
      
      16, or SEQ ID NO;
      
      17.
  - 35. The composition of claim 24, wherein the antibody comprises a VL sequence of SEQ ID NO:
    - 18, SEQ ID NO;
      
      19, SEQ ID NO;
      
      20, SEQ ID NO;
      
      21, SEQ ID NO;
      
      22, or SEQ ID NO;
      
      34.
  - 36. The composition of claim 24, wherein the antibody comprises a VH sequence of SEQ ID NO:
    - 15 and a VL sequence of SEQ ID NO;
      
      18.
  - 37. The composition of claim 24, wherein the antibody comprises a VH sequence of SEQ ID NO:
    - 15 and a VL sequence of SEQ ID NO;
      
      19.
  - 38. The composition of claim 24, wherein the antibody comprises a VH sequence of SEQ ID NO:
    - 27 and a VL sequence of SEQ ID NO;
      
      20.
  - 39. The composition of claim 24, wherein the antibody comprises a VH sequence of SEQ ID NO:
    - 16 and a VL sequence of SEQ ID NO;
      
      21.
  - 40. The composition of claim 24, wherein the antibody comprises a VH sequence of SEQ ID NO:
    - 17 and a VL sequence of SEQ ID NO;
      
      22.
  - 41. The composition of claim 24, wherein the antibody comprises a VH sequence of SEQ ID NO:
    - 17 and a VL sequence of SEQ ID NO;
      
      34.
  - 42. The composition of claim 24, wherein the antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO:
    - 35 and a light chain comprising the amino acid sequence of SEQ ID NO;
      
      36, (ii) a heavy chain comprising amino acids 1-450 of SEQ ID NO;
      
      35 and a light chain comprising the amino acid sequence of SEQ ID NO;
      
      36, (iii) a heavy chain comprising amino acids 1-449 of SEQ ID NO;
      
      35 and a light chain comprising the amino acid sequence of SEQ ID NO;
      
      36, or (iv) the heavy and light chain of any one of (i), (ii), or (iii) wherein the proline at amino acid position 449 of SEQ ID NO;
      
      35 is amidated.

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Current Assignee
F Hoffmann-La Roche AG (Roche Holding AG)
Original Assignee
Genentech, Inc. (Roche Holding AG)
Inventors
Wu, Yan, Kirchhofer, Daniel K., Li, Wei, Lam, Xanthe M., Chiu, Cecilia Pui Chi, Peterson, Andrew, Kolumam, Ganesh A., Beltran, Monica Kong, Moran, Paul, Luis, Lin, Hui, Ada
Primary Examiner(s)
Gangle, Brian J
Assistant Examiner(s)
MCCOLLUM, ANDREA K

Application Number

US13/918,755
Publication Number

US 20130344085A1
Time in Patent Office

984 Days
Field of Search

None
US Class Current

1/1
CPC Class Codes

A61K 2039/505   comprising antibodies

A61K 39/39591   Stabilisation, fragmentation

A61P 3/06   Antihyperlipidemics

A61P 43/00   Drugs for specific purposes...

C07K 16/40   against enzymes

C07K 2317/34   Identification of a linear ...

C07K 2317/55   Fab or Fab'

C07K 2317/76   Antagonist effect on antige...

C07K 2317/92   Affinity (KD), association ...

C07K 2317/94   Stability, e.g. half-life, ...

Anti-PCSK9 antibodies, formulations, dosing, and methods of use

First Claim

2 Assignments

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Abstract

111 Citations

42 Claims

Specification

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Anti-PCSK9 antibodies, formulations, dosing, and methods of use

First Claim

2 Assignments

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Accused Products

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Abstract

111 Citations

42 Claims

Specification

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